Lu and Wang Cancer Commun (2018) 38:63 https://doi.org/10.1186/s40880-018-0336-6 Cancer Communications REVIEW Open Access Nonmetabolic functions of metabolic enzymes in cancer development Sean Lu and Yugang Wang* Abstract Metabolism is a fundamental biological process composed of a series of reactions catalyzed by metabolic enzymes. Emerging evidence demonstrates that the aberrant signaling in cancer cells induces nonmetabolic functions of meta- bolic enzymes in many instrumental cellular activities, which involve metabolic enzyme-mediated protein post-trans- lational modifcations, such as phosphorylation, acetylation, and succinylation. In the most well-researched literatures, metabolic enzymes phosphorylate proteins rather than their metabolites as substrates. Some metabolic enzymes have altered subcellular localization, which allows their metabolic products to directly participate in nonmetabolic activities. This review discusses how these fndings have deepened our understanding on enzymes originally classi- fed as metabolic enzymes, by highlighting the nonmetabolic functions of several metabolic enzymes responsible for the development of cancer, and evaluates the potential for targeting these functions in cancer treatment. Keywords: Metabolic enzymes, Function, Protein kinase, Metabolite products, Phosphorylation, Acetylation, Succinylation, Mitochondria Introduction reactions in which they were originally characterized to Metabolism, regulated by metabolic enzymes, supports work on. For instance, several metabolic enzymes use cell growth and proliferation by providing energy for cel- proteins as substrates and function as protein kinases lular activities and synthesizing the molecular building to phosphorylate these protein substrates, thereby regu- blocks for production of amino acids, nucleotides, and lating diverse functions [1]. Second, metabolic enzymes lipids. Metabolic enzymes are responsible for specifc that translocate from their original subcellular compart- chemical reactions on metabolites, which takes place ments to diferent organelles, where their metabolite under strict regulation at specifc subcellular locations products are directly used for protein modifcations or in the metabolic cascades. Metabolic enzymes, such as acting as instrumental regulators for other proteins. For carboxylases, dehydrogenases, lipoxygenases, oxidore- instance, mitochondrial α-ketoglutarate dehydrogenase ductases, kinases, lyses, and transferases carry out a wide (α-KGDH) that translocates to the nucleus and produces range of catalytic activities and are responsible for a vari- succinyl-coenzyme A (CoA), which is used by the histone ety of cellular functions necessary for cellular homeosta- acetyltransferase, lysine acetyltransferase 2A (KAT2A), to sis and survival. succinylate histone H3 [2, 3]. In addition, mitochondrial Recent literatures have determined that some meta- fumarase, when translocated to the nucleus, produces bolic enzymes possess nonmetabolic activities that are fumarate that inhibits lysine demethylase 2B (KDM2B) critical in the development of cancer. Tese nonmetabolic histone demethylase activity and enhances the methyla- activities can be divided into two categories. First, meta- tion of histone H3 and the repair of damaged DNA [4]. bolic enzymes that use non-metabolites as substrates to Tis review summarizes the recent fndings regarding catalyze reactions that are distinct from the metabolic these nonmetabolic functions of metabolic enzymes and highlights the implication of these functions in cancer development. *Correspondence: [email protected] Brain Tumor Center and Department of Neuro‑Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lu and Wang Cancer Commun (2018) 38:63 Page 2 of 7 Metabolic enzymes function as protein kinases of the cytokinesis process, and proliferation of tumor Protein kinases are critical regulators of intracellular cells [16]. In addition, it has been found that in hepato- signal transduction pathways that mediate various cel- cellular carcinoma (HCC), PKM2 phosphorylates the lular processes in both unicellular and multicellular sterol regulatory element-binding proteins (SREBPs) at organisms. Tey can directly transfer the γ-phosphate Tr59, activates lipid biosynthesis, and promotes the pro- from adenosine triphosphate (ATP) to specifc tyros- liferation of the cancer cells [17]. Apart from its functions ine (Tyr), serine (Ser), threonine (Tr), and histidine in regulating gene expression and cell cycle progression, (His) residues on substrate proteins, thereby altering PKM2 has been demonstrated to phosphorylate serine/ the functions of these substrates. More than 500 protein threonine kinase 1 (AKT1) at Ser202/203 to release it kinases have been identifed in humans, constituting of from the regulatory-associated protein of mTOR (rap- about 1.7% of all human genes [5]. Recent studies have tor), which subsequently promotes hormonal and nutri- demonstrated that several metabolic enzymes, such as ent signaling-independent activation of the mammalian pyruvate kinase M2 (PKM2), phosphoglycerate kinase 1 target of rapamycin complex 1 (mTORC1), to provide (PGK1), ketohexokinase-A (KHK-A), hexokinases (HK), survival and proliferation advantages over normal cell nucleoside diphosphate kinase (NDPK or NDK), and upon stimulus by the epidermal growth factor receptor 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (EGFR)-dependent activation of nuclear factor kappa (PFKFB4), have unexpected protein kinase activities and enhancer binding protein (NF-κB) [6, 18]. play signifcant roles in nonmetabolic cellular functions. In response to oxidative stress, PKM2 promotes cell Tese new studies expand the family of protein kinases survival by translocating into the mitochondria, phos- and provide new insights into the integrated regulation of phorylating the apoptosis regulator Bcl2 at Tr69 to sta- cell metabolism and other cellular processes. bilize Bcl2, which blocks its association with Cul3-based E3 ligase to prevent the degradation of Bcl2 and pro- PKM2 motes the resistance of tumor cells against apoptosis [19]. Pyruvate kinase (PK) catalyzes the fnal rate-limiting step Further, as PKM2 can also phosphorylate the synapto- of glycolysis and converts phosphoenolpyruvate (PEP) to some-associated protein 23 (SNAP23) at Ser95, resulting pyruvate by transferring a phosphate group from PEP to in the formation of the soluble N-ethylmaleimide sensi- adenosine diphosphate (ADP), producing ATP. It has four tive factor attachment protein receptors (SNARE) com- isoforms: PKL, PKR, PKM1, and PKM2. PKM2 is highly plex, this demonstrates that PKM2 has contribution in expressed in cancer cells [6]. Besides, although PKM1 has the remodeling of the tumor microenvironments by pro- a higher glycolytic activity than PKM2, only the protein moting tumor cell exosome secretions, which are neces- kinase activity of PKM2 has been described till present. sary for the docking of tumor cells to plasma membranes PKM2 is involved in the regulation of gene expression, [20]. A recent report has shown that in pancreatic ductal mitosis, apoptosis, and other critical cellular activities adenocarcinoma, PKM2 could phosphorylate the ser- that promote aerobic glycolysis and tumor growth [7–9]. ine/threonine protein kinase PAK2 at Ser20, Ser141, and PKM2’s protein kinase activity was initially identifed Ser 192/197 to recruit heat shock protein 90 for increas- from the phosphorylation of histone H3 at Tr11 and ing the stability of the PAK2 protein, thereby promoting that of signal transducer and activator of transcription invasion and metastasis of the pancreatic cancerous cells 3 (STAT3) at Tyr705. In the nucleus, PKM2-mediated [21]. Further, PKM2 was observed to promote genomic histone H3 phosphorylation promotes β-catenin- and instability, an important hallmark of cancer develop- c-Myc-mediated gene expression, which enhances aero- ment and progression due to increased interruption of bic glycolysis and promotes the proliferation of tumor DNA repair, in breast cancer cells breast cancer since cells [10–14]. During mitosis, PKM2 binds to the spindle it was demonstrated that nuclear PKM2 could interact checkpoint protein Bub3 and phosphorylate it at Tyr207 with and directly phosphorylate histone H2AX at Ser139 to enable the interaction of the Bub3–Bub1 complex with under DNA damaged conditions to induce chromosomal kinetochores, which is essential for the mitotic/spindle- aberrations and promote cancer cell proliferation [22]. assembly checkpoint, accurate chromosome segregation, Furthermore, phosphoproteomic studies in yeast and and tumorigenesis [15]. PKM2 also phosphorylates myo- mammalian cells have revealed that hundreds of addi- sin light chain 2 (MLC2) at Tyr118, primes the binding tional proteins, including many protein kinases such as of Rho-associated protein kinase 2 (ROCK2) to